Twist expression in normal mammary epithelial cells triggered EMT and simultaneously upregulated expression of mammary cancer stem cell markers. Parallel studies by others have reinforced the notion that EMT drives tumor progression, metastasis, drug resistance, and a “stem-like” phenotype. With respect to bladder cancers, recent studies implicated EMT in disease progression, invasion/Fulvestrant migration, and resistance to radiation and targeted therapy. With these observations in mind, we expected that measuring EMT marker expression would identify the most lethal subset of muscle-invasive bladder cancers. Our results confirm that EMT markers were elevated in muscle-invasive cancers. Strikingly, however, increased p63 expression was associated with adverse outcomes both in muscleinvasive and in T1 tumors. Several recent studies have shown that EMT and “stem-like” phenotype is regulated by micro RNAs. miR-205 and the miR-200 family can maintain the epithelial phenotype by suppressing the expression of mesenchymal transcription factors. Interestingly, we have recently discovered that DNp63 directly promotes miR205 expression providing an explanation for the tight correlation between expression of DNp63 and epithelial markers in bladder cancer cell lines and primary tumors. We are also investigating DNp63’s effects on bladder cancer cell biology in order to better understand why its expression correlates with poor patient survival. Although structurally similar to p53, p63 is phylogenetically older than its cousin and displays much higher inter-species conservation. Furthermore, even though p53 and p63 interact with similar DNA sequence motifs, most p63 isoforms do not transactivate p53 target genes but rather can function as dominant negatives suppressing p53-dependent transactivation. P63 is expressed at high levels in the basal layers containing the normal stem cell compartments in many different epithelial tissues, including the urothelium. Targeted ablation of p63 expression disrupts normal bladder differentiation in the mouse, leading to loss of the basal/suprabasal layer with selective retention of so-called “umbrella” cells. These observations have led many investigators to propose that p63 is essential for the maintenance of self-renewal and/or survival of normal stem cells. Thus, p63 expression in muscle-invasive disease may be associated with both epithelial phenotype. However, cells within the normal urothelium express TAp63, which would be expected to have very different effects on cell biology. Strikingly, our preliminary studies indicate that stable knockdown of DNp63 in bladder cancer cells causes strong inhibition of proliferation, effects that are associated with downreguliation of c-Myc mRNA and protein expression. Therefore, we currently favor the idea that DNp63’s significance as a negative prognostic marker is related to its effects on tumor cell proliferation. Additional mechanistic studies are required to define the relationships between the EMT phenotype, “stemness”, proliferation, drug sensitivity, and metastasis in preclinical models and primary tumors. Whereas one cannot discount the contribution of socioeconomic factors, such as a more advanced stage of disease at diagnosis in AAs, other biological factors also contribute to the progression of colon cancer.